Trophy papers

Getting a paper into certain journals is good for one's career. These papers usually represent impressive and important work. It seems that many more such manuscripts are produced than the number that can be published in high-profile journals, such as Nature. It's probably not a bad thing to submit a manuscript to a high-profile journal if you think you have a chance there, but these attempts often generate considerable frustration, for reasons ranging from peculiar formatting requirements to rejection without peer review. Some researchers believe in a piece of work so much that they are not deterred by these frustrations and keep submitting to one high-profile journal after another. This enthusiasm is admirable, but if repeated attempts fail, then the level of frustration can become rather high because of the wasted effort. I wonder how others handle this sort of situation. Do you put more work into the project? Do you submit to an open-access journal? Do you move on to the next desirable target journal and take on the significant non-scientific work, such as figure layout and reference formatting, which a manuscript revision can sometimes entail? Do you wonder if the manuscript is fatally flawed because of the initial attempt to present the findings in a highly concise format? Please share your thoughts and experiences. Should we even be trying to do more than simply sharing our findings?